The MIC range of butenafine against dermatophytes is 0.03-0.25 μg/ml, indicating significant activity against them. Malassezia furfur is not affected by it, and it exhibits negligible activity against Candida albicans [1]. Promastigote forms of L were eliminated by butenafine (25, 50, or 100 μM). L. amazonensis and L. braziliensis in a dose-dependent fashion, exhibiting EC50 values in BALB peritoneal macrophages of 34.10 ± 3.76 μM, respectively. and mice at 81.25±10.24 μM/c. With a CC50 of 97.88 μM, butenafine exhibits mild cytotoxicity on peritoneal macrophages in BALB/c mice [1].

There is no effect of mouse butenafine (subcutaneous injection; 1-100 mg/kg) on the autonomic or central nervous systems. The somatic nervous system of guinea pigs after topical treatment of 0.3–3.0% butenafine solution is unaffected [1]. Butenafine (1% topical; 4–10 days; days 3 and 4 postinfection) was successful in vivo against dermatophytosis, Trichophyton mentagrophytes after 10 days Complete cure in a preliminary treatment study conducted in guinea pigs [1]. There is no difference in the efficacy between treating dermatophytosis, Trichophyton mentagrophytes in vivo, once daily or twice daily. Butenafine (0.125, 0.25, 0.5, and 1.0% applied topically; once daily or twice daily; day 4 postinfection) demonstrated 100% cure after application at 0.5% or 1%, and 1% per dose.

Absorption, Distribution and Excretion
The total amount absorbed through the skin into the systemic circulation has not been quantified.

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Metabolism / Metabolites
The primary metabolite in urine was formed through hydroxylation at the terminal t-butyl side-chain.

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Biological Half-Life
Following topical application, a biphasic decline of plasma butenafine concentrations was observed with the half-lives estimated to be 35 hours initial and over 150 hours terminal.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Topical butenafine has not been studied during breastfeeding. Because it is poorly absorbed after topical application, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.[1]
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Katrina Kokjohn, et al. Evaluation of in vitro activity of ciclopirox olamine, butenafine HCl and econazole nitrate against dermatophytes, yeasts and bacteria.Int J Dermatol. 2003 Sep;42 Suppl 1:11-7.
[2]. Adriana Bezerra-Souza, et al. The antifungal compound butenafine eliminates promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis. 2016 Dec;65(6 Pt A):702-707.
[3]. Topical Antifungal Agent. Butenafine

Butenafine is trimethylamine in which hydrogen atoms attached to different methyl groups are substituted by 1-naphthyl and 4-tert-butylphenyl groups. It is an inhibitor of squalene epoxidase, an enzyme responsible for the creation of sterols needed in fungal cell membranes, and is used as its hydrochloride salt for treatment of dermatological fungal infections. It has a role as an EC 1.14.13.132 (squalene monooxygenase) inhibitor and an antifungal drug. It is a tertiary amine and a member of naphthalenes.
Butenafine hydrochloride is a synthetic benzylamine antifungal agent. Butenafine's mechanism of action is believed to involve the synthesis inhibition of sterols. In particular, butenafine acts to inhibit the activity of the squalene epoxidase enzyme that is essential in the formation of sterols necessary for fungal cell membranes.
Butenafine is a Benzylamine Antifungal.
See also: Butenafine Hydrochloride (has salt form).

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Drug Indication
For the topical treatment of the following dermatologic infections: tinea (pityriasis) versicolor due to M. furfur, interdigital tinea pedis (athlete’s foot), tinea corporis (ringworm) and tinea cruris (jock itch) due to E. floccosum, T. mentagrophytes, T. rubrum, and T. tonsurans.
FDA Label

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Mechanism of Action
Although the mechanism of action has not been fully established, it has been suggested that butenafine, like allylamines, interferes with sterol biosynthesis (especially ergosterol) by inhibiting squalene monooxygenase, an enzyme responsible for converting squalene to 2,3-oxydo squalene. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Blockage of squalene monooxygenase also leads to a subsequent accumulation of squalene. When a high concentration of squalene is reached, it is thought to have an effect of directly kill fungal cells.

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Pharmacodynamics
Butenafine is a synthetic antifungal agent that is structurally and pharmacologically related to allylamine antifungals. The exact mechanism of action has not been established, but it is suggested that butenafine's antifungal activity is exerted through the alteration of cellular membranes, which results in increased membrane permeability, and growth inhibition. Butenafine is mainly active against dermatophytes and has superior fungicidal activity against this group of fungi when compared to that of terbinafine, naftifine, tolnaftate, clotrimazole, and bifonazole. It is also active against Candida albicans and this activity is superior to that of terbinafine and naftifine. Butenafine also generates low MICs for Cryptococcus neoformans and Aspergillus spp. as well.

C23H27N

317.46718

317.214

101828-21-1

Butenafine Hydrochloride;101827-46-7

2484

Typically exists as solid at room temperature

1.0±0.1 g/cm3

426.1±14.0 °C at 760 mmHg

187.7±17.0 °C

0.0±1.0 mmHg at 25°C

1.598

6.77

0

1

5

24

374

0

ABJKWBDEJIDSJZ-UHFFFAOYSA-N

InChI=1S/C23H27N/c1-23(2,3)21-14-12-18(13-15-21)16-24(4)17-20-10-7-9-19-8-5-6-11-22(19)20/h5-15H,16-17H2,1-4H3

1-(4-tert-butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl)methanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)